NM_021147.5(CCNO):c.258_262dup (p.Gln88fs) AND Primary ciliary dyskinesia 29

Germline classification:: Pathogenic (5 submissions)
Last evaluated:: Sep 22, 2024
Review status:: 2 stars out of maximum of 4 stars
criteria provided, multiple submitters, no conflicts

Somatic classification of clinical impact:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Somatic classification of oncogenicity:: None
Review status:: (0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided

Record status:: current
Accession:: RCV000128541.19

Allele description [Variation Report for NM_021147.5(CCNO):c.258_262dup (p.Gln88fs)]

NM_021147.5(CCNO):c.258_262dup (p.Gln88fs)

Genes:

LOC129993895:ATAC-STARR-seq lymphoblastoid silent region 16013 [Gene]
CCNO:cyclin O [Gene - OMIM - HGNC]

Variant type:

Microsatellite

Cytogenetic location:

5q11.2

Genomic location:

Preferred name:

NM_021147.5(CCNO):c.258_262dup (p.Gln88fs)

HGVS:

NC_000005.10:g.55233261_55233262insGGGCC
NC_000005.10:g.55233266CGGGC[3]
NG_034201.1:g.5447GGCCC[3]
NM_021147.5:c.258_262dupMANE SELECT
NP_066970.3:p.Gln88fs
NC_000005.9:g.54529089_54529090insGGGCC
NC_000005.9:g.54529094CGGGC[3]
NM_021147.4:c.258_262dup
NM_021147.4:c.258_262dupGGCCC
NP_066970.3:p.Gln88ArgfsTer8
NR_125346.2:n.338GGCCC[3]
NR_125347.2:n.338GGCCC[3]

Protein change:

Q88fs

Links:

OMIM: 607752.0002; dbSNP: rs587777499

NCBI 1000 Genomes Browser:

rs587777499

Molecular consequence:

NM_021147.5:c.258_262dup - frameshift variant - [Sequence Ontology: SO:0001589]
NR_125346.2:n.338GGCCC[3] - non-coding transcript variant - [Sequence Ontology: SO:0001619]
NR_125347.2:n.338GGCCC[3] - non-coding transcript variant - [Sequence Ontology: SO:0001619]

Condition(s)

Name:: Primary ciliary dyskinesia 29
Synonyms:: CILIARY DYSKINESIA, PRIMARY, 29, WITHOUT SITUS INVERSUS
Identifiers:: MONDO: MONDO:0014378; MedGen: C4014534; Orphanet: 244; OMIM: 615872

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Submission Accession	Submitter	Review Status (Assertion method)	Clinical Significance (Last evaluated)	Origin	Method	Citations
SCV000172184	OMIM	no assertion criteria provided	Pathogenic (Jun 1, 2014)	germline	literature only	PubMed (2) [See all records that cite these PMIDs] 24747639, 24824133
SCV002016970	Revvity Omics, Revvity	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 29, 2021)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV002779842	Fulgent Genetics, Fulgent Genetics	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Apr 25, 2022)	unknown	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV004175747	Neuberg Centre For Genomic Medicine, NCGM	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Mar 1, 2023)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]
SCV005374431	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	criteria provided, single submitter (ACMG Guidelines, 2015)	Pathogenic (Sep 22, 2024)	germline	clinical testing	PubMed (1) [See all records that cite this PMID]

Help

Summary from all submissions

Ethnicity	Origin	Affected	Individuals	Families	Chromosomes tested	Number Tested	Family history	Method
not provided	germline	not provided	not provided	not provided	not provided	not provided	not provided	literature only
not provided	unknown	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	yes	not provided	not provided	not provided	not provided	not provided	clinical testing
not provided	germline	unknown	not provided	not provided	not provided	not provided	not provided	clinical testing

Citations

PubMed

Mutations in CCNO result in congenital mucociliary clearance disorder with reduced generation of multiple motile cilia.

Wallmeier J, Al-Mutairi DA, Chen CT, Loges NT, Pennekamp P, Menchen T, Ma L, Shamseldin HE, Olbrich H, Dougherty GW, Werner C, Alsabah BH, Köhler G, Jaspers M, Boon M, Griese M, Schmitt-Grohé S, Zimmermann T, Koerner-Rettberg C, Horak E, Kintner C, Alkuraya FS, et al.

Nat Genet. 2014 Jun;46(6):646-51. doi: 10.1038/ng.2961. Epub 2014 Apr 20.

PubMed [citation]

PMID:: 24747639

Unexpected genetic heterogeneity for primary ciliary dyskinesia in the Irish Traveller population.

Casey JP, McGettigan PA, Healy F, Hogg C, Reynolds A, Kennedy BN, Ennis S, Slattery D, Lynch SA.

Eur J Hum Genet. 2015 Feb;23(2):210-7. doi: 10.1038/ejhg.2014.79. Epub 2014 May 14.

PubMed [citation]

PMID:: 24824133
PMCID:: PMC4297907

See all PubMed Citations (3)

Details of each submission

From OMIM, SCV000172184.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	literature only	PubMed (2)

Description

In 4 affected individuals from 2 unrelated consanguineous families with primary ciliary dyskinesia-29 (CILD29; 615872), Wallmeier et al. (2014) identified a homozygous 5-bp duplication (c.258_262dupGGCCC) in exon 1 of the CCNO gene, resulting in a frameshift and premature termination (Gln88ArgfsTer7). The mutation segregated with the disorder in the families and was not present in the 1000 Genomes Project database.

In 2 brothers of Irish Traveller descent with CILD29, Casey et al. (2015) identified homozygosity for the same 5-bp duplication (c.258_262dup) in the CCNO gene, which they predicted would result in a Gln88ArgfsTer8 substitution. The mutation, which was found by a combination of homozygosity mapping and exome variant analysis, was confirmed by Sanger sequencing. The mutation segregated with the disorder in the family.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	not provided	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Revvity Omics, Revvity, SCV002016970.3

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Fulgent Genetics, Fulgent Genetics, SCV002779842.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	unknown	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Neuberg Centre For Genomic Medicine, NCGM, SCV004175747.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

Description

The frameshift c.258_262dup (p.Gln88ArgfsTer8) variant in CCNO gene has been reported previously in homozygous and compound heterozygous state in individuals affected with primary ciliary dyskinesia (Wallmeier et al. 2014; Casey et al. 2015; Davis et al. 2019). This variant segregated with disease in families consistently with autosomal recessive inheritance (Wallmeier et al. 2014). The p.Gln88ArgfsTer8 variant is reported with an allele frequency of 0.01% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submissions). This variant causes a frameshift starting with codon Glutamine 88, changes this amino acid to Arginine residue, and creates a premature Stop codon at position 8 of the new reading frame, denoted p.Gln88ArgfsTer8. This variant is predicted to cause loss of normal protein function through protein truncation. Loss of function variants have been previously reported to be disease causing. For these reasons, this variant has been classified as Pathogenic.

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	yes	not provided	not provided	not provided		not provided	not provided	not provided	not provided

From Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center, SCV005374431.1

#	Ethnicity	Individuals	Chromosomes Tested	Family History	Method	Citations
1	not provided	not provided	not provided	not provided	clinical testing	PubMed (1)

#	Sample				Method		Observation
#	Origin	Affected	Number tested	Tissue	Purpose	Method	Individuals	Allele frequency	Families	Co-occurrences
1	germline	unknown	not provided	not provided	not provided		not provided	not provided	not provided	not provided

Last Updated: Nov 10, 2024

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